Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Abstract

Efforts to improve the anti-tumor response to KRAS^G12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRAS^G12C inhibitor (KRAS^G12Ci) to those induced by KRAS^G12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS^G12Ci induces an anti-tumor response stronger than that observed with KRAS^G12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRAS^G12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRAS^G12Ci-resistant CRC models. Our findings position KRAS^G12C plus SOS1 inhibition therapy as a promising strategy for treating both KRAS^G12C-mutated tumors as well as for addressing acquired resistance to KRAS^G12Ci.